Renoprotective Effects of Low‐dose Metformin Treatment in a Mouse Model of Diabetic Kidney Disease

Abstract

Background Diabetes mellitus (DM) affects more than 30 million people in the United States. About one‐third of DM patients develop diabetic kidney disease (DKD). Metformin is a widely prescribed antidiabetic medication for patients with type 2 diabetes; however, its direct effects on renal function are poorly understood. Hence, our study aimed to investigate the effects of a non‐glucose lowering, low‐dose metformin treatment against the progression of DKD using a genetic mouse model of type 2 diabetes. Methods Our study utilized db/db mice, which spontaneously develop type 2 diabetes due to a mutation in leptin receptors. To aggravate the degree of renal injury, each mouse had its left kidney removed at ten weeks of age. Heterozygous, non‐diabetic mice were used as the control group. The study had four treatment groups: 1) vehicle‐treated control, 2) metformin‐treated control, 3) diabetic, vehicle‐treated, and 4) diabetic, metformin‐treated. Mice were treated with either vehicle or metformin (100 mg/kg/day) for four weeks. Urine and kidney tissue samples were collected at the end of the study to measure the markers of renal dysfunction, such as elevations in urine albumin‐creatinine ratio (UACR) and kidney injury molecule 1 (KIM‐1), and the markers of renal fibrosis, such as transforming growth factor‐beta (TGF‐β) and alpha‐smooth muscle actin (α‐SMA). Results Our results indicate that low‐dose metformin‐treatment decreased UACR (117.53 ± 61.56 vs. 205.3 ± 112.5); however, it did not alter the elevated fasting blood glucose levels or plasma creatinine levels in diabetic mice. Kidneys from metformin‐treated diabetic mice revealed reduced KIM‐1 immunostaining (1.5 ± 0.5 vs. 2.3 ± 0.7) compared to vehicle‐treated diabetic mice. Similarly, the metformin‐treated diabetic mice kidneys showed decreased immunostaining for TGF‐β (0.7 ± 0.2 vs. 1.3 ± 0.3). Moreover, the renal protein expression of α‐SMA (assessed via western blotting) was significantly reduced in metformin‐treated diabetic mice than the vehicle‐treated counterparts. Conclusion Our findings suggest that low‐dose metformin treatment ameliorates renal dysfunction and fibrosis associated with DKD. Future studies are warranted to ascertain the renoprotective effects of low‐dose Metformin treatment against the progression of DKD.